Cisplatin (cis-Diaminedichloroplatinum (II); hereinafter abbreviated as CDDP) is a very effective carcinostatic agent in a medical practice, but it is known that it has very strong side effects such as nephrotoxicity. Further, when CDDP is administered in blood, it is quickly excreted to the outside of the body by glomerular filtration, and therefore the blood half-time thereof is very short. Accordingly, a lot of pharmaceutical preparations have so far been tried to be developed by many researchers in order to extend this blood half-time of CDDP and reduce nephrotoxicity, but the existing situation is that the successful examples thereof have not yet been achieved.
Thus, it is the existing situation that in general, a suitable transfusion is administered before administering a CDDP agent and that CDDP is then mixed with a large amount of a physiological salt solution or a glucose-salt solution and it is intravenously dripped in several hours.
Accordingly, strongly desired to be developed is a pharmaceutical preparation which makes it possible to carry out a new administering form in place of complicated and time-consuming intravenous drip, for example, bolus intravenous administration.
In order to meet such desire, the present inventors proposed a polymeric metal complex micelle obtained by forming a complex of poly(ethylene glycol)-poly(α,β-aspartic acid) (hereinafter abbreviated as PEG-P(Asp)) with CDDP in an aqueous medium (for example, Yokoyama; Kataoka et al., J. Controlled Release 39 (1996) 351–356; Nishiyama; Kataoka et al., Langmuir 1999, 15, 377–383). The above polymeric metal complex micelle maintains a stable micelle structure in refined water over a long period of time and slowly releases a Pt (II) complex in a physiological salt solution (0.15M NaCl solution) of 37° C., and it can maintain a polymer micelle structure over a period of about 10 hours. That is, attentions have to be paid to this metal complex micelle in the point that it can be present under physiological environment, for example, in blood circulation over a considerably long period of time. Further, it is indicated that when carrying out intravenous administration, the above metal complex micelle provides a carcinostatic effect and a nephrotoxicity-reducing effect which are excellent as compared with those of a CDDP simple substance (for example, Kataoka, PHARM TECH JAPAN Vol. 16, No. 8 (2000) 1209 to 1219).
However, desire to development of a pharmaceutical preparation which can maintain, if possible, a polymer micelle form under physiological environment over further longer period of time shall still be present. Accordingly, an object of the present invention is to provide a polymeric metal complex which can maintain a polymer micelle form under physiological environment over further longer period of time than the foregoing polymeric metal complex micelle of PEG-P(Asp) with CDDP.